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In this study, we hypothesized that androgen-deprivation therapy (ADT) in prostate cancer, although initially efficient, induces changes in the tumor kinome, which subsequently promote development of castration-resistant (CR) disease. Recognizing the correlation between tumor hypoxia and poor prognosis in prostate cancer, we further hypothesized that such changes might be influenced by hypoxia. Microarrays with 144 kinase peptide substrates were applied to analyze CWR22 prostate carcinoma xenograft samples from ADT-naïve, androgen-deprived (AD), long-term AD (ADL), and CR disease stages. The impact of hypoxia was assessed by matching the xenograft kinase activity profiles with those acquired from hypoxic and normoxic prostate carcinoma cell cultures, whereas the clinical relevance was evaluated by analyzing prostatectomy tumor samples from patients with locally advanced disease, either in ADT-naïve or early CR disease stages. By using this novel peptide substrate microarray method we revealed high kinase activity mediated by signal transducer and activator of transcription 5A (STAT5A) in CR prostate cancer. Additionally, we uncovered high STAT5A kinase activity already in regressing ADL xenografts, before renewed CR growth was evidenced. Finally, since increased STAT5A kinase activity also was detected after exposing prostate carcinoma cells to hypoxia, we propose long-term ADT to induce tumor hypoxia and stimulate STAT5A kinase activity, subsequently leading to renewed CR tumor growth. Hence, the study detected STAT5A as a candidate to be further investigated for its potential as marker of advanced prostate cancer and as possible therapeutic target protein. [ABSTRACT FROM AUTHOR]

Objective: The PRevention of cArdiac Dysfunction during Adjuvant breast cancer therapy (PRADA) study is a randomized, placebo-controlled, double-blind trial to determine whether angiotensin receptor blockers (ARB), or beta-blockers or their combination may prevent the development of left ventricular (LV) dysfunction in patients on standard adjuvant treatment for early breast cancer. Methods: Following surgical resection, 120 breast cancer patients scheduled for adjuvant epirubicin-containing chemotherapy and, if indicated, trastuzumab, will be included. They will be randomized to an ARB (candesartan), a beta-blocker (metoprolol) and matching placebos in a 2 × 2 factorial design. The primary objective of the PRADA study is to assess whether prophylactic ARB and/or beta-blockers may prevent a reduction in LV ejection fraction (EF) after adjuvant treatment of early breast cancer, as evaluated by serial cardiovascular magnetic resonance (CMR) performed at randomization, after the first chemotherapy cycle and on its completion, and for subgroups, on completion of radiotherapy or trastuzumab. Secondary outcome measures include echocardiographic indices of LV diastolic dysfunction, structural myocardial alterations assessed by CMR and changes in cardiac biomarkers. Conclusion: PRADA may provide new information on the prophylactic effect of ARB and beta-blockers in patients with early breast cancer regarding the risk of developing cardiac dysfunction from adjuvant cancer treatment. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background. Signet-ring cell carcinoma (SRCC) is an uncommon tumor entity in rectal cancer, often considered to be resistant to non-surgical therapy. In locally advanced primary or recurrent rectal cancer, diagnostic information from magnetic resonance imaging (MRI) is considered superior in planning the optimal treatment strategy, which usually includes preoperative radiotherapy. The recognition of MRI features that correlate with the radiation response might ultimately be used to select patients for tailored treatment and, in addition, avoid potentially toxic therapy in non-responding patients. Material and methods. In a cohort of 120 rectal cancer patients who had received preoperative radiotherapy (50 Gy in 2 Gy fractions), six patients were noted to have SRCC tumor differentiation. Initial diagnostic MRI examination included assessment of local T- and N-stage and tumor morphology. Histological tumor response was subsequently assessed in the resected specimens, and postoperative follow-up data was compiled until disease recurrence. Results. Following the preoperative radiotherapy, two distinctly different histological responses – complete response (ypT0N0) or no response – were observed. Extensive mesorectal lymph node metastasis (N2 disease) at the pretreatment MRI examination was unambiguously associated with lack of response and rapid development of disseminated disease. Importantly, patients with complete response have been observed for 23–52 months postoperatively without evidence of recurrent disease. Discussion. Our review may suggest that patients with locally advanced growth of rectal SRCC, despite poorer outcome when compared to patients with conventional-type rectal adenocarcinoma, when presenting limited lymph node disease should be offered preoperative radiotherapy in a tentatively curative setting. [ABSTRACT FROM AUTHOR]